Hetero compound

Abstract

To provide a useful compound as an active ingredient for a preventing and/or treating agent for rejection in the transplantation of an organ, bone marrow, or a tissue, an autoimmune disease, or the like, which has an excellent S1P 1 agonist activity. Since the compound of the invention has an S1P 1 agonist activity, it is useful as an active ingredient for a treating or preventing agent for a disease caused by unfavorable lymphocytic infiltration, for example, an autoimmune disease such as graft rejection in the transplantation of an organ, bone marrow, or a tissue, a graft-versus-host disease, rheumatic arthritis, multiple sclerosis, systemic lupus erythematosus, a nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, pulmonary disorder, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, or an inflammatory disease, and further, a disease caused by the abnormal growth or accumulation of cells such as cancer and leukemia.

1. A compound selected from the following, or a pharmaceutically acceptable salt thereof:
 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy]phenyl)-1,2,4-oxadiazol-3-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride; 
 2-[4-(5-{5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine-3-yl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide; or 
 2-[4-(5-{5-chloro-6-[2-fluoro-1-(fluoromethyl)ethoxy]pyridin-3-yl]-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl)acetamide. 
 
     
     
       2. A method for treating rejection in transplantation of organ, bone marrow or tissue in human or animal, graft-versus-host disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, nephrotic syndrome, encephalomeningitis, myasthenia gravis, pancreatitis, hepatitis, nephritis, diabetes, asthma, atopic dermatitis, inflammatory bowel disease, atherosclerosis, ischemia-reperfusion injury, comprising steps of administering to a patient in need thereof a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A is 
       
       
         
           
           
               
               
           
         
         X is a single bond, —CH 2 —, —NR 3 —, —O—, —S—, —S(═O)— or —S(═O) 2 —, 
         R 1  is halogen, aryl, heteroaryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )heterocycloalkyl, or optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 2 -C 8 )alkenyl, wherein the optional substituents are halogen, —CONH 2 , aryl or (C 3 -C 8 )cycloalkyl; 
         R 2  is —CN, —O—(C 1 -C 6 )alkyl, —C(═O)H, halogen or optionally substituted (C 1 -C 6 )alkyl, wherein the optional substituents are halogen or —OH, and when —X— is a single bond, R 1  and R 2  may in combination form a 5-membered ring optionally substituted with (C 1 -C 6 )alkyl groups; 
         R 3  is —H, wherein R 3  may form morpholino, 1-pyrrolidinyl or 3,4-dehydropiperidin-1-yl, together with R 1  and nitrogen; 
         R 4  is 
       
       
         
           
           
               
               
           
         
       
       wherein any one of bonds from an R 4  ring is bound to the oxadiazole ring;
 R 5  is —H, R 0 —(C 1 -C 6 )alkyl, R 0 —(C 1 -C 6 )alkyl-O—, R 0 —(C 1 -C 6 )alkyl-C(═O)—, R 0 —(C 1 -C 6 )alkyl-S(═O) 2 —, R 0 —O—(C 1 -C 6 )alkyl-, R 0 —C(═O)—(C 1 -C 6 )alkyl-, R 0 —S(═O) 2 —(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, —C(═O)H, —OR X , —S(═O) 2 R X , halogen, ═O, —NR X R Y , or —C(═O)NR X R Y , wherein (C 1 -C 6 )alkyl means (C 1 -C 6 )alkyl which may be substituted with at least one group selected from R 0 ; 
 R 0  is —CN, —C(═O)NR X R Y , —NHR x , —SR x , —S(═O) 2 R x  or —OR x ; and 
 R X  and R Y  are independently —H, or (C 1 -C 6 )alkyl which may be optionally substituted with —OH, —NH 2 , —NHC(═O)OC(CH 3 ) 3  or heteroaryl, 
 wherein —NR X R Y , —C(═O)NR X R Y , or —C(═O)NR X R Y  in R 5 , R X  and R Y  may form morpholino or piperadino, together with nitrogen, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       3. A method for treating multiple sclerosis, comprising the steps of administering to a patient in need thereof a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A is 
       
       
         
           
           
               
               
           
         
         X is a single bond, —CH 2 —, —NR 3 —, —O—, —S—, —S(═O)— or —S(═O) 2 —; 
         R 1  is halogen, aryl, heteroaryl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 3 -C 8 )heterocycloalkyl, or optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 2 -C 8 )alkenyl, wherein the optional substituents are halogen, —CONH 2 , aryl or (C 3 -C 8 )cycloalkyl; 
         R 2  is —CN, —O—(C 1 -C 6 )alkyl, —C(═O)H, halogen or optionally substituted (C 1 -C 6 )alkyl, wherein the optional substituents are halogen or —OH, and when —X— is a single bond, R 1  and R 2  may in combination form a 5-membered ring optionally substituted with (C 1 -C 6 )alkyl groups; 
         R 3  is —H, wherein R 3  may form morpholino, 1-pyrrolidinyl or 3,4-dehydropiperidin-1-yl, together with R 1  and nitrogen; 
         R 4  is 
       
       
         
           
           
               
               
           
         
       
       wherein any one of bonds from an R 4  ring is bound to the oxadiazole ring;
 R 5  is —H, R 0 —(C 1 -C 6 )alkyl, R 0 —(C 1 -C 6 )alkyl-O—, R 0 —(C 1 -C 6 )alkyl-C(═O)—, R 0 —(C 1 -C 6 )alkyl-S(═O) 2 —, R 0 —O—(C 1 -C 6 )alkyl-, R 0 —C(═O)—(C 1 -C 6 )alkyl-, R 0 —S(═O) 2 —(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl-, —C(═O)H, —OR X , —S(═O) 2 R X , halogen, ═O, —NR X R Y , or —C(═O)NR X R Y , wherein (C 1 -C 6 )alkyl means (C 1 -C 6 )alkyl which may be substituted with at least one group selected from R 0 ; 
 R 0  is —CN, —C(═O)NR X R Y , —NHR x , —SR x , —S(═O) 2 R x  or —OR x ; and 
 R X  and R Y  are independently —H, or (C 1 -C 6 )alkyl which may be optionally substituted with —OH, —NH 2 , —NHC(═O)OC(CH 3 ) 3  or heteroaryl, 
 wherein —NR X R Y , —C(═O)NR X R Y , or —C(═O)NR X R Y  in R 5 , R X  and R Y  may form morpholino or piperadino, together with nitrogen, 
 or a pharmaceutically acceptable salt thereof.